Dataset Information

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

ABSTRACT:

Background

Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies.

Methods

We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB.

Results

Flow cytometry reveals a notable presence of CD45^hi/CD11b^hi macrophage-like and CD45^int/CD11b^int microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (T_regs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45^hi/CD11b^hi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor-cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target.

Conclusions

This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA-VSIG axis to enhance anti-tumor responses.

SUBMITTER: Munoz Perez N

PROVIDER: S-EPMC11312086 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

Muñoz Perez Natalia N Pensabene Juliana M JM Galbo Phillip M PM Sadeghipour Negar N Xiu Joanne J Moziak Kirsten K Yazejian Rita M RM Welch Rachel L RL Bell W Robert WR Sengupta Soma S Aulakh Sonikpreet S Eberhart Charles G CG Loeb David M DM Eskandar Emad E Zheng Deyou D Zang Xingxing X Martin Allison M AM

Cancers 20240724 15

<h4>Background</h4>Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies.<h4>Methods</h4>We utilize a syngeneic mouse model to investigate the tumor immune mi ...[more]

PMID: 39123357

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Dataset Information

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

Background

Methods

Results

Conclusions

Publications

VISTA Emerges as a Promising Target against Immune Evasion Mechanisms in Medulloblastoma.

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